News Release

LA JOLLA, CA – April 22,
2013 – In a serendipitous discovery, scientists at The Scripps Research
Institute (TSRI) have found a way to turn bone marrow stem cells directly into
brain cells.

Current techniques for
turning patients’ marrow cells into cells of some other desired type are relatively
cumbersome, risky and effectively confined to the lab dish. The new finding points
to the possibility of simpler and safer techniques. Cell therapies derived from
patients’ own cells are widely expected to be useful in treating spinal cord
injuries, strokes and other conditions throughout the body, with little or no
risk of immune rejection.

“These results highlight
the potential of antibodies as versatile manipulators of cellular functions,”
said Richard A. Lerner, the Lita Annenberg Hazen Professor of Immunochemistry and
institute professor in the Department of Cell and Molecular Biology at TSRI,
and principal investigator for the new study. “This is a far cry from the way
antibodies used to be thought of—as molecules that were selected simply for
binding and not function.”

The researchers
discovered the method, reported in the online Early Edition of the Proceedings
of the National Academy of Sciences the week of April 22, 2013, while
looking for lab-grown antibodies that can activate a growth-stimulating
receptor on marrow cells. One antibody turned out to activate the receptor in a
way that induces marrow stem cells—which normally develop into white blood
cells—to become neural progenitor cells, a type of almost-mature brain cell.

Nature’s Toolkit

Natural antibodies are large,
Y-shaped proteins produced by immune cells. Collectively, they are diverse
enough to recognize about 100 billion distinct shapes on viruses, bacteria and
other targets. Since the 1980s, molecular biologists have known how to produce
antibodies in cell cultures in the laboratory. That has allowed them to start
using this vast, target-gripping toolkit to make scientific probes, as well as
diagnostics and therapies for cancer, arthritis, transplant rejection, viral
infections and other diseases.

In the late 1980s, Lerner
and his TSRI colleagues helped invent the first techniques for generating large
“libraries” of distinct antibodies and swiftly determining which of these could
bind to a desired target. The anti-inflammatory antibody Humira®, now one of the
world’s top-selling drugs, was discovered with the benefit of this technology.

Last year, in a study spearheaded
by TSRI Research Associate Hongkai Zhang, Lerner’s laboratory devised a new
antibody-discovery technique—in which antibodies are produced in mammalian cells
along with receptors or other target molecules of interest. The technique
enables researchers to determine rapidly not just which antibodies in a library
bind to a given receptor, for example, but also which ones activate the
receptor and thereby alter cell function.

Lab Dish in a Cell

For the new study, Lerner
laboratory Research Associate Jia Xie and colleagues modified the new technique
so that antibody proteins produced in a given cell are physically anchored to
the cell’s outer membrane, near its target receptors. “Confining an antibody’s
activity to the cell in which it is produced effectively allows us to use
larger antibody libraries and to screen these antibodies more quickly for a
specific activity,” said Xie. With the improved technique, scientists can sift
through a library of tens of millions of antibodies in a few days.

In an early test, Xie
used the new method to screen for antibodies that could activate the GCSF
receptor, a growth-factor receptor found on bone marrow cells and other cell
types. GCSF-mimicking drugs were among the first biotech bestsellers because of
their ability to stimulate white blood cell growth—which counteracts the
marrow-suppressing side effect of cancer chemotherapy.

The team soon isolated
one antibody type or “clone” that could activate the GCSF receptor and
stimulate growth in test cells. The researchers then tested an unanchored,
soluble version of this antibody on cultures of bone marrow stem cells from
human volunteers. Whereas the GCSF protein, as expected, stimulated such stem
cells to proliferate and start maturing towards adult white blood cells, the
GCSF-mimicking antibody had a markedly different effect.

“The cells proliferated, but also started becoming long and thin and attaching to
the bottom of the dish,” remembered Xie.

To Lerner, the cells were
reminiscent of neural progenitor cells—which further tests for neural cell
markers confirmed they were.

A New Direction

Changing cells of marrow
lineage into cells of neural lineage—a direct identity switch termed
“transdifferentiation”—just by activating a single receptor is a noteworthy achievement.
Scientists do have methods for turning marrow stem cells into other adult cell
types, but these methods typically require a radical and risky deprogramming of
marrow cells to an embryonic-like stem-cell state, followed by a complex series
of molecular nudges toward a given adult cell fate. Relatively few laboratories
have reported direct transdifferentiation techniques.

“As far as I know, no one
has ever achieved transdifferentiation by using a single protein—a protein that
potentially could be used as a therapeutic,” said Lerner.

Current cell-therapy methods
typically assume that a patient’s cells will be harvested, then reprogrammed
and multiplied in a lab dish before being re-introduced into the patient. In
principle, according to Lerner, an antibody such as the one they have
discovered could be injected directly into the bloodstream of a sick patient. From the bloodstream it would find its
way to the marrow, and, for example, convert some marrow stem cells into neural
progenitor cells. “Those neural progenitors would infiltrate the brain, find
areas of damage and help repair them,” he said.

While the researchers
still aren’t sure why the new antibody has such an odd effect on the GCSF
receptor, they suspect it binds the receptor for longer than the natural GCSF protein
can achieve, and this lengthier interaction alters the receptor’s signaling
pattern. Drug-development researchers are increasingly recognizing that subtle
differences in the way a cell-surface receptor is bound and activated can
result in very different biological effects. That adds complexity to their
task, but in principle expands the scope of what they can achieve. “If you can
use the same receptor in different ways, then the potential of the genome is
bigger,” said Lerner.

In addition to Lerner and
Xie, contributors to the study, “Autocrine
Signaling Based Selection of Combinatorial Antibodies That Transdifferentiate
Human Stem Cells,” were Hongkai Zhang of the Lerner Laboratory, and Kyungmoo
Yea of The Scripps Korea Antibody Institute, Chuncheon-si, Korea.

Funding
for the study was provided by The Scripps Korea Antibody Institute and Hongye
Innovative Antibody Technologies (HIAT).

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 2,700 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.